Macrophages activated in vivo and in vitro display increased capacity to kill microorganisms and tumor cells. We characterized a major macrophage surface glycoprotein (gp160) on nonactivated macrophages and found that cell surface expression of gp160 is dramatically decreased on macrophages activated in vivo. Down-regulation of gp160 expression on activation in vivo was shown to extend to the level of synthesis. gp160 synthesis is negligible in macrophages activated in vivo relative to nonactivated macrophages. We plan to investigate the mechanisms underlying down-regulation of gp160 expression and synthesis by examining macrophages activated in vitro. Using a panel of monoclonal antibodies raised against gp160 and related surface glycoproteins, we will characterize the intracellular precursor molecule and find out whether alterations occur at the level of transcription, translation, or post-translation. We will test the hypothesis that gp160 is a functional participant in the macrophage activation process using specific antibody and chemical modification of the unique plasmin-sensitive site on gp160. To probe its function, we will characterize gp160 structurally through a variety of probes of the molecule in its native configuration in the plasma membrane, correlated with splicing of the affinity-purified molecule and analysis of its fragments. These studies will allow us to analyze and dissect the cellular events of macrophage activation which play a fundamental role in immunological defense against certain infectious and neoplastic diseases. (MB)